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Background: Influenza A (H3N2) clade 3C.3a was the predominant influenza virus in Israel throughout the 2018-2019 season, constituting a drift from the influenza A (H3N2) vaccine. We estimated the end-of season vaccine effectiveness (VE) by age, among community patients with influenza-like illness (ILI), considering the hemagglutinin (HA) gene mutations and amino acid substitutions of influenza A (H3N2) viruses detected. Methods: Nose-throat samples were analyzed for the presence of influenza virus, type/subtype, and HA gene sequence. HA gene sequences and amino acid substitutions were compared to the influenza A/Singapore/INFIMH-16-0019/2016 (H3N2)-like 2018-2019 vaccine virus, and a phylogenetic tree was generated. Influenza VE against influenza A (H3N2) was estimated using the test-negative design. VE was estimated by age group and by 15 year moving age intervals. Results: In total, 90% of the influenza A (H3N2) viruses belonged to the 3C.3a clade, constituting a unique situation in the northern hemisphere. Adjusted all-age influenza A (H3N2) VE was −3.5% (95% CI: −51.2 to 29.1). Although adjusted VEs were very low among infants, children, and young adults, a VE of 45% (95% CI: −19.2 to 74.6) was estimated among adults aged ≥45 years old. Conclusions: The higher VE point estimates among older adults may be related to previous exposure to similar influenza viruses.

Background Rhabdomyolysis with influenza infection is rarely reported in adults. We report here influenza A induced rhabdomyolysis and anterior compartment syndrome (ACS). Case report This case report describes a 43-year-old woman exhibiting influenza A induced rhabdomyolysis. High levels of creatine kinase (97,000IU/L) and high titer of anti-influenza A virus antibody (H3N2) (320×) with negative anti-influenza B virus antibody were observed. T2 fat suppression muscle MRI imaging showed high-intensity signals in rectus femoris, vastus lateralis, adductor magnus, and semimembranosus (SM) muscles. The existence of ACS was suspected out. Muscle biopsy showed that fiber size variations exist without infiltration of inflammatory cells. The symptoms and muscle MRI findings of T2 fat suppression imaging was markedly improved. Conclusions Muscle MRI T2 fat suppression imaging is a useful method to monitor influenza A induced rhabdomyolysis. We should keep in mind the possibilities of rhabdomyolysis and ACS in patients with influenza A infection presenting serious muscle pain.

BACKGROUND: Currently used trivalent influenza vaccines (TIVs) contain two strains of influenza A and one strain of influenza B. However, co-circulation of two distinct B lineages and difficulties in predicting which lineage will predominate in the next season have led to frequent B-strain mismatches. Newly registered quadrivalent influenza vaccines (QIVs) include two B strains and might therefore provide wider protection. Objectives: To evaluate the cost-effectiveness of using QIV versus TIV for routine influenza vaccination in the United States (US) during the next 20 years. Methods: A dynamic transmission model was used to estimate the additional protection offered by QIV over TIV against symptomatic influenza B disease. Subsequently, we used a decision tree model to determine the costeffectiveness of replacing TIV with QIV from a societal perspective. US data on influenza-related disease outcomes and corresponding costs were derived from published sources (e. g. Molinari et al. 2007). Results: Over 20 years, replacing TIV with QIV is predicted to prevent 13.3 million influenza B cases. According to our model this resulted in a reduction of 113,000 hospitalizations and 13,200 deaths. Moreover, 200,000 quality- adjusted life-years (QALYs), US$3.1 billion in medical costs and US$0.6 billion in indirect costs were saved. The base case estimate of the incremental cost-effectiveness ratio (ICER) was US$29,000 per QALY gained. Economic parameters with highest impact on the ICER were vaccine price, QALY loss due to influenza and probability of hospitalization or death given symptomatic infection. Conclusions: Introducing QIV into the immunization program of the United States would prevent a substantial number of hospitalizations and deaths. Moreover, cost-effectiveness was shown to be favorable when a cost-effectiveness threshold of US$50,000 is applied.

Background: Current influenza vaccines mainly induce immune responses against viral membrane glycoproteins, which undergo continuous mutations through antigenic drift. To prevent immune escape, annual vaccination with the latest predicted viral strains is adopted. Such vaccination strategy is inconvenient and cost-inefficient. Moreover, poor protective effectiveness is observed when there is antigenic mismatch between vaccine strains and actual epidemic strains. This is especially of concern during a pandemic outbreak, when large populations are affected by the newly re-assorted viral strain derived from antigenic shift. Objectives: To design phase IIb studies to evaluate the safety, immunogenicity and cross-seasonal clinical efficacy of two universal influenza vaccines (Flu-v and M-001) targeting different conserved epitopes of influenza viruses. The tested epitopes are identified from the viral surface glycoproteins as well as the viral internal (structural) proteins. Moreover, these epitopes are consistently expressed on both influenza A and B viruses. Methods: In two separate trials, a total of 1500 healthy adults will be recruited from multiple centers in Europe and randomized to receive placebo or the tested influenza vaccines at low or high antigen doses through a double-blind procedure. Two parenteral administrations will be given with a 21 day interval. In one trial, additional administrations of pandemic influenza vaccine will be given 21 and 42 days after the second administration. Clinical symptom scores and adverse events (AEs) will be collected from AE diary card. Humoral and cellular immune correlates of protection will be assessed. The (severity of) incident RT-PCR-confirmed influenza infection will be recorded over two subsequent influenza seasons. Conclusions: Universal influenza vaccines are urgently needed to increase protection among vulnerable groups. Vaccine trial design needs to incorporate safety, correlates of protection and clinical efficacy.

Background: Current influenza vaccines mainly induce immune responses against viral membrane glycoproteins, which undergo continuous mutations through antigenic drift. To prevent immune escape, annual vaccination with the latest predicted viral strains is adopted. Such vaccination strategy is inconvenient and cost-inefficient. Moreover, poor protective effectiveness is observed when there is antigenic mismatch between vaccine strains and actual epidemic strains. This is especially of concern during a pandemic outbreak, when large populations are affected by the newly re-assorted viral strain derived from antigenic shift. Objectives: To design phase IIb studies to evaluate the safety, immunogenicity and cross-seasonal clinical efficacy of two universal influenza vaccines (Flu-v and M-001) targeting different conserved epitopes of influenza viruses. The tested epitopes are identified from the viral surface glycoproteins as well as the viral internal (structural) proteins. Moreover, these epitopes are consistently expressed on both influenza A and B viruses. Methods: In two separate trials, a total of 1500 healthy adults will be recruited from multiple centers in Europe and randomized to receive placebo or the tested influenza vaccines at low or high antigen doses through a double-blind procedure. Two parenteral administrations will be given with a 21 day interval. In one trial, additional administrations of pandemic influenza vaccine will be given 21 and 42 days after the second administration. Clinical symptom scores and adverse events (AEs) will be collected from AE diary card. Humoral and cellular immune correlates of protection will be assessed. The (severity of) incident RT-PCR-confirmed influenza infection will be recorded over two subsequent influenza seasons. Conclusions: Universal influenza vaccines are urgently needed to increase protection among vulnerable groups. Vaccine trial design needs to incorporate safety, correlates of protection and clinical efficacy.

Objectives: Vaccination has proven to be an efficient preventive strategy against influenza infection. Each year, two genetically distinct influenza B lineages cocirculate. Current trivalent influenza vaccines (TIVs) contain only one influenza B and two influenza A strains, but vaccine mismatch are frequent due to the difficulty to predict which B lineage will predominate during the next epidemic. Recently licensed quadrivalent influenza vaccines (QIVs) containing a strain from each B lineage should address these issues, but their impact still needs to be estimated. Our study assesses retrospectively what would have been the public health benefit of routinely vaccinating the US population with QIV instead of TIV. Methods: We developed a dynamic compartmental model able to account for interactions between influenza B lineages (natural or vaccine-induced). The model simulates influenza dynamics for the period 2000-2014, to account for the long-term impact of infection and vaccination. Age-structured population dynamics, vaccine efficacy (VE) per strain, and weekly ramp-up of vaccination coverage are modelled. Sensitivity analyses were performed on VE, duration of immunity, levels of vaccine-induced cross-protection between B strains. Results: Assuming a cross-protection of 70% of the matched VE, the model predicts that QIV would have prevented on average 15% more B-lineages cases. Elderly people (65+yo) and young seniors (50-64yo) benefit the most from QIV with 21% and 18% reduction of B cases respectively in those age groups. Reducing the cross-protection estimate of the matched VE to 50%, 30%, and 0% improves the relative benefit of QIV to 25%, 30%, and 34% fewer B cases in the US. Conclusions: Using a realistic retrospective framework, with real-life vaccine mismatch, our analysis shows that routine vaccination with QIV has the potential to substantially reduce the number of influenza infections, even with relatively conservative estimates of TIV induced cross-protection.

Objectives: Trivalent influenza vaccine (TIV) contains two Influenza A strains, but only one of the two B-lineages, resulting in frequent mismatches between vaccines and circulating B-lineages during seasonal epidemics. Quadrivalent influenza vaccine (QIV) prevents such mismatches by including both B-lineages. The objective of our study was to estimate the cost-effectiveness (CE) of QIV versus TIV in Germany by coupling influenza incidence generated by a dynamic individualbased simulation to health and economic outcomes. Methods: An individualbased simulation tool (known in the literature as 4FLU) was refined to estimate the impact of TIV and QIV on clinical infection incidence per year and age over 20 calendar years in Germany. Cases were subsequently linked to health and economic outcomes. Inputs were gathered from national databases and published literature. Vaccination rates reflect the current coverage in Germany; 2014 was used as the baseline year for costs. The productivity costs (societal perspective) were calculated according to the human capital approach. Costs and effects were discounted at 3% and 1.5%, respectively. Univariate and probabilistic sensitivity analyses were performed. Results: Per 100,000 inhabitants, QIV prevents 6,803 more clinical influenza cases and 6.45 more deaths than TIV, accumulated in 20 years. From the societal perspective, QIV dominates TIV, with € 1,424,323 of cost savings and 152 QALYs gained (98 QALYs by preventing clinical cases and 54 QALYs by avoiding premature mortality). These results are sensitive to changes in perspective, vaccination coverage, vaccine prices, productivity cost approach and discount rates, yet favorable CE remains. Conclusions: Based on our analysis, QIV is expected to be cost-effective, or even cost-saving in Germany. Our results are in line with findings from other studies using dynamic models and for other settings.

Background: Current influenza vaccines mainly induce immune responses against viral membrane glycoproteins, which undergo continuous mutations through antigenic drift. To prevent immune escape, annual vaccination with the latest predicted viral strains is adopted. Such vaccination strategy is inconvenient and cost-inefficient. Moreover, poor protective effectiveness is observed when there is antigenic mismatch between vaccine strains and actual epidemic strains. This is especially of concern during a pandemic outbreak, when large populations are affected by the newly re-assorted viral strain derived from antigenic shift. Objectives: To design phase IIb studies to evaluate the safety, immunogenicity and cross-seasonal clinical efficacy of two universal influenza vaccines (Flu-v and M-001) targeting different conserved epitopes of influenza viruses. The tested epitopes are identified from the viral surface glycoproteins as well as the viral internal (structural) proteins. Moreover, these epitopes are consistently expressed on both influenza A and B viruses. Methods: In two separate trials, a total of 1500 healthy adults will be recruited from multiple centers in Europe and randomized to receive placebo or the tested influenza vaccines at low or high antigen doses through a double-blind procedure. Two parenteral administrations will be given with a 21 day interval. In one trial, additional administrations of pandemic influenza vaccine will be given 21 and 42 days after the second administration. Clinical symptom scores and adverse events (AEs) will be collected from AE diary card. Humoral and cellular immune correlates of protection will be assessed. The (severity of) incident RT-PCR-confirmed influenza infection will be recorded over two subsequent influenza seasons. Conclusions: Universal influenza vaccines are urgently needed to increase protection among vulnerable groups. Vaccine trial design needs to incorporate safety, correlates of protection and clinical efficacy.